Mechanisms of O2 transport and circulation-metabolism coupling are studied in red, postural muscles and in epicardium. O2 saturation of myoglobin (Mb) and hemoglobin (Hb) is measured with a new cryomicrospectrophotometric method; spatial resolution is on the order of 1-2 mitochondria. Longitudinal intracapillary )2 gradients, transcapillary gradients, and probability densities of capillary PO2 will be used to evaluate diffusive and convective O2 shunting, and the contribution of Hb and plasma boundary layer resistances to O2 mass transfer. Maps of O2 gradients in single skeletal muscle cells and in small cell culsters will evaluate interaction of diffusion fields and the tissue-cell component of "resistance" to O2 transport. The above will test proposed new concepts of O2 exchange and several new functions of Mb. O2 gradients and probability densities of PO2 in skeletal-muscle cells for various conditions of work and O2 supply will be related to flow, functional capillary density and tissue metabolites to: a) define metabolic signals in rest-work-rest transitions, b) set an upper bound on the critical PO2 for VO2 in vivo, c) relate tissue PO2 to work intensity and d) determine the effect of the motor unit organization of skeletal muscle on O2 delivery. Results to date suggest that metabolic signals do not initiate exercise hyperemia, or capillary recruitment. We shall therefore test the hypothesis that vasodilation is initiated by intrinsic peptidergic vasodilator nerves. Probability densities of cell and capillary PO2 will be used to evaluate O2 delivery to epicardium in normoxia, hyperoxemia and in animal models of physiologic and pathologic cardiac hypertrophy. Since O2 lack underlies much of pathophysiology the research proposed should promote the prevention and rational treatment of cardiovascular disease.